CN108101823A - A kind of preparation method of high chiral purity lactam intermediate and Bu Waxitan - Google Patents

A kind of preparation method of high chiral purity lactam intermediate and Bu Waxitan Download PDF

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Publication number
CN108101823A
CN108101823A CN201810148128.0A CN201810148128A CN108101823A CN 108101823 A CN108101823 A CN 108101823A CN 201810148128 A CN201810148128 A CN 201810148128A CN 108101823 A CN108101823 A CN 108101823A
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China
Prior art keywords
preparation
structural formula
compounds
lactam intermediate
palladium
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CN201810148128.0A
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Chinese (zh)
Inventor
于振鹏
肖飞
王国平
戚淑娴
高贺
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Yangzhou Lian Ao Bio Pharmaceutical Co Ltd
Yangzhou Miracle Pharmaceutical Co Ltd
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Yangzhou Lian Ao Bio Pharmaceutical Co Ltd
Yangzhou Miracle Pharmaceutical Co Ltd
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Priority to CN201810148128.0A priority Critical patent/CN108101823A/en
Publication of CN108101823A publication Critical patent/CN108101823A/en
Priority to CN201811465520.4A priority patent/CN109516943B/en
Priority to EP18906460.3A priority patent/EP3778568B1/en
Priority to US17/059,125 priority patent/US11952341B2/en
Priority to PCT/CN2018/121624 priority patent/WO2019157856A1/en
Priority to CA3103280A priority patent/CA3103280C/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention discloses the preparation methods of a kind of high chiral purity lactam intermediate and Bu Waxitan.The present invention provides a kind of preparation methods of lactam intermediate structural formula D compounds, include the following steps：In a solvent, by heavy metal catalyst and chiral induction agent, compound C is reduced to lactam intermediate D by hydrogenating reduction.Bu Waxitan can be prepared in a lactam intermediate structural formula D compounds only step using the present invention, and synthetic route is short, and reaction condition is mild, and post processing is simple, and reaction yield is high, and chiral selectivity is good, and manufacturing cost is low.For the conversion ratio of compound C up to 81%, the de values of compound D are suitable for industrialized production up to more than 99% in reaction process.

Description

A kind of preparation method of high chiral purity lactam intermediate and Bu Waxitan
Technical field
The present invention relates to organic synthesis fields, and specifically, the present invention provides a kind of high chiral purity lactam intermediates Preparation method and Bu Waxitan preparation method.
Background technology
Bu Waxitan (Brivaracetam), entitled (the 2S) -2- [(4R) -2- oxo -4- propyl -1- pyrrolidinyls] of chemistry Butyramide, structural formula are as follows：
Bu Waxitan was the third generation antiepileptic developed by Belgian UCB. S.A. (BE) Bruxelles Belgium, respectively in January, 2016 and 2 months Obtain EMEA and FDA approval listings, for treating the breaking-out of the part of adult and 16 years old or more teenager epileptic, with or not companion There is the auxiliary treatment of secondary generalized seizure.
The preparation process of Bu Waxitan is broadly divided into three classes at present, and one kind is former to grind the technique that UCB is representative and need chirality Chromatography post separation isomers, it is higher to equipment requirement, production cost is greatly increased, for example patent CN1882535A discloses one kind The preparation method of Bu Waxitan, finally obtained is the mixture of Bu Waxitan and its diastereoisomer, it is necessary to pass through (CHIRALPAK AD 20um) chiral stationary phase, n-hexane/ethyl alcohol (45/55, V/V) is eluant, eluent, above-mentioned by chromatographic isolation Mixture can just obtain the higher Bu Waxitan of purity, can not mass produce.One kind synthesizes for chiral source method, such method Long there are reaction scheme by taking CN106432030A as an example, intermediate activity is high, it is difficult to purify, be prone to disappear in reaction process The shortcomings of rotation, be unfavorable for quality control and cost control, one kind is Split Method, by enzyme, the methods of chemical reagent split in acyl Amine intermediate, but such method is longer generally there are route, complex steps shortcomings, especially chemical resolution method, resolving agent Introducing it is particularly disadvantageous for the quality control of product, accordingly, there exist to simple and cost-effective preparation high-purity Bu Waxi The demand of smooth method, to obtain the Bu Waxitan of high-optical-purity.
The content of the invention
The object of the present invention is to provide a kind of preparation methods of high chiral purity lactam intermediate.
In order to realize foregoing invention purpose, the preparation method of high chiral purity lactam intermediate of the present invention uses following skill Art scheme：
A kind of preparation method of lactam intermediate structural formula D compounds, structural formula C compounds in a solvent, pass through weight Metallic catalyst and chiral induction agent, hydrogenating reduction obtain lactam intermediate structural formula D compounds
Further, the solvent is selected from water, methanol, ethyl alcohol, isopropanol, propyl alcohol, butanol, isobutanol, acetone, tetrahydrochysene The mixture of furans, acetonitrile and Yi Shang solvent.It is preferred that water.
Further, the heavy metal catalyst is selected from palladium carbon, palladium, platinum carbon, platinum, ruthenium carbon, rhodium carbon, palladium aluminium oxide, palladium Silica, palladium barium carbonate, palladium calcium carbonate, hydroxide palladium carbon, palladium dioxide.It is preferred that palladium carbon.
Further, the chiral induction agent be formic acid, citric acid, malonic acid, succinic acid, 1,3,5-triazines -2,4, The mixture of tri- thioketones trisodium salts of 6- (cas 17766-26-6) or more.Optimization citric acid.
Further, the quality of the chiral induction agent and the mass ratio of compound C are no more than 5.Described in preferred The quality of chiral induction agent is no more than 3 with the mass ratio of compound C；The quality and chemical combination of the preferred chiral induction agent The mass ratio of object C is no more than 1.
Further, the Hydrogen Vapor Pressure is no more than 5bar, and the reaction temperature is -20~50 DEG C.Reaction temperature is excellent Select 0~30 DEG C.
Another object of the present invention is to provide a kind of preparation method of Bu Waxitan.
In order to realize foregoing invention purpose, the preparation method of Bu Waxitan of the present invention adopts the following technical scheme that：
The present invention provides a kind of preparation methods of Bu Waxitan, include the following steps：It is obtained according to above-mentioned preparation method Lactam intermediate structural formula D compounds mix structural formula D compounds with solvent, add in activator, are passed through ammonia reaction, Up to Bu Waxitan.
Further, the activator be thionyl chloride, oxalyl chloride, phosphorus oxychloride, mesyl chloride, preferably methylsulfonyl Chlorine, the solvent are halogenated hydrocarbons, and the reaction temperature is -20~30 DEG C, preferably -10~0 DEG C.Such as activator is changed to The response situations such as HATU, HBTU are good, but have remaining HOAT, HOBT residuals, it is not easy to remove.
Compared with prior art, the beneficial effects of the present invention are：
1st, chiral chromatogram post separation isomers need not be used in preparation process, is only extracted, washs drying, concentration step Suddenly can separating effective ingredient, separation process is simple, and at low cost；
2nd, reaction intermediate solid-state is easy to further purify using recrystallization method；
3rd, without high-temperature high-voltage reaction, safety easy to operate in reaction synthesis；
4th, by adding chiral induction agent in reaction process, reaction diastereoisomer selectivity can be greatly improved, it is former The material more conventional reduction method of conversion ratio doubles, and avoids using expensive unconventional chiral auxiliary.
5th, the intermediate de values synthesized by this law are more than 99%, it is only necessary to which simple recrystallization can either meet the isomery of API Body control requirement.
Specific embodiment
With reference to embodiment, the present invention is furture elucidated, it should be understood that these embodiments are merely to illustrate this It invents rather than limits the scope of the invention, after the present invention has been read, those skilled in the art are various to the present invention's The modification of equivalent form falls within the application scope as defined in the appended claims.
Embodiment 1
The preparation of compound D
Monohydrate potassium (50g 0.237mol) is added in into tetra- mouthfuls of reaction bulbs of 1L, water 500ml stirring and dissolvings add in 5% palladium carbon 5g, stirring add in chemical formula C compounds 50g (0.237mol), 30 DEG C of temperature control, and hydrogen is replaced, and Hydrogen Vapor Pressure is 2bar is stirred to react, when reaction 20 is small after, control to raw material disappears complete in TLC, stops reaction, filtering, and 2M hydrochloric acid adjusts pH= 2,5 DEG C are cooled to, filtering, 50ml water washings obtain white solid 46g, are recrystallized, obtained white solid with methyl tertiary butyl ether(MTBE) 100ml Body 41g (0.192mol), yield 81%, HPLC 99.52%, de%99.2%.
Embodiment 2
The preparation of compound D
Malonic acid 12g (0.115mol) is added in into tetra- mouthfuls of reaction bulbs of 1L, water 250ml isopropanol 250ml stirring and dissolvings add Enter 10% palladium carbon 5g, stir, add in chemical formula C compounds 50g (0.237mol), 30 DEG C of temperature control, hydrogen is replaced, and Hydrogen Vapor Pressure is 4bar is stirred to react, when reaction 20 is small after, control to raw material disappears complete in TLC, stops reaction, filtering, and 2M hydrochloric acid adjusts pH= 2,5 DEG C are cooled to, is filtered, 50ml water washings, crude product is recrystallized with methyl tertiary butyl ether(MTBE) 100ml, obtains white solid 44g (0.206mol), yield 87%, HPLC99.23%, de%99.1%.
Embodiment 3
The preparation of compound D
Monohydrate potassium 20g (0.095mol) is added in into 500ml reaction bulbs, water 100ml stirring and dissolvings add in 10% Palladium carbon 0.5g, adds in 1,3,5-triazines -2,4, and tri- thioketones trisodium salt 0.0001g of 6- stir after addition, add chemical formula Cization Close object 10g (0.047mol), 5 DEG C of temperature control, hydrogen displacement, Hydrogen Vapor Pressure 5bar is stirred to react, when reaction 20 is small after, in TLC Control to raw material disappears completely, stops reaction, and filtering adjusts pH=2 with 2M hydrochloric acid, is cooled to 5 DEG C, filters, 20ml water washings, slightly Product are recrystallized with methyl tertiary butyl ether(MTBE) 20ml, obtain white solid 8.1g (0.038mol), yield 82%, HPLC95.6%, de% 99.1%.
Embodiment 4
The preparation of compound D
Malonic acid 9.8g (0.094mol) is added in into 500ml reaction bulbs, water 100ml methanol 100ml stirring and dissolvings add in 10% palladium carbon 10g, stirring add in chemical formula C compounds 20g (0.094mol), -10 DEG C of temperature control, and hydrogen is replaced, and Hydrogen Vapor Pressure is 1bar is stirred to react, when reaction 25 is small after, control to raw material disappears complete in TLC, stops reaction, 40 DEG C of rotations are except organic solvent, mistake Filter, 2M hydrochloric acid adjust pH=2, are cooled to 5 DEG C, filter, 20ml water washings, and crude product is recrystallized with methyl tertiary butyl ether(MTBE) 40ml, is obtained White solid 17g (0.079mol), yield 86%, HPLC86.2%, de%99.3%.
Embodiment 5
The preparation of compound D
Formic acid 1.1g (0.024mol) is added in into tetra- mouthfuls of reaction bulbs of 500ml, water 100ml ethyl alcohol 100ml stirring and dissolvings add Enter 5% platinum carbon 0.25g, add in 1,3,5-triazines -2,4, tri- thioketones trisodium salt 0.0001g of 6-, stirring adds in chemical formula C chemical combination Object 10g (0.047mol), -20 DEG C of temperature control, hydrogen displacement, Hydrogen Vapor Pressure 5bar is stirred to react, when reaction 32 is small after, in TLC Control to raw material disappears completely, stops reacting, filtering, and 40 DEG C of rotations remove reaction solution, and 2M hydrochloric acid adjusts pH=2, is cooled to 5 DEG C, filters, 10ml water washings, crude product are recrystallized with methyl tertiary butyl ether(MTBE) 20ml, obtain white solid 8.5g (0.040mol), yield 85%, HPLC93.1%, de%99.5%.
Embodiment 6
The preparation of compound D
Succinic acid 21g (0.176mol) is added in into 500ml reaction bulbs, water 200ml isopropanol 100ml stirring and dissolvings add Enter 10% palladium carbon 0.5g, add in 1,3,5-triazines -2,4, tri- thioketones trisodium salt 0.01g of 6-, stirring adds in chemical formula C compounds 7g (0.033mol), -20 DEG C of temperature control, hydrogen displacement, Hydrogen Vapor Pressure 5bar is stirred to react, when reaction 40 is small after, controlled in TLC It disappearing to raw material complete, stops reacting, filtering, 40 DEG C of rotations adjust pH=2 except organic solvent, 2M hydrochloric acid, are cooled to 5 DEG C, filter, 20ml water washings, crude product are recrystallized with methyl tertiary butyl ether(MTBE) 40ml, obtain white solid 15.7g (0.074mol), yield 79%, HPLC93.3%, de%99.1%.
Embodiment 7
The preparation of compound D
Monohydrate potassium 5g (0.0238mol) is added in into 500ml reaction bulbs, methanol 300ml stirring and dissolvings add in 10% palladium carbon 2.5g, stirring add in 1,3,5-triazines -2,4, tri- thioketones trisodium salt 0.0005g of 6-, and stirring adds in chemical formula Cization Close object 50g (0.237mol), -10 DEG C of temperature control, hydrogen displacement, Hydrogen Vapor Pressure 5bar is stirred to react, when reaction 30 is small after, TLC Middle control to raw material disappears completely, stops reaction, filtering, and 40 DEG C of rotations remove solvent, water 200ml, ethyl acetate are added in steaming excess 200ml is extracted, ethyl acetate phase, is extracted with 200ml 1M sodium hydrate aqueous solutions, and water mutually uses 6M salt under the conditions of 10~20 DEG C Acid for adjusting pH=2 cool down 5 DEG C, and white solid, filtering is precipitated, and crude product is recrystallized with methyl tertiary butyl ether(MTBE) 100ml, obtained white solid Body 39g (0.183mol), yield 77%, HPLC97.65%, de%99.2%.
Embodiment 8
The preparation of Bu Waxitan
Compound D 40g (0.188mol) are added in into 500ml reaction bulbs, dichloromethane 240ml is stirred molten after addition Solution, reaction temperature control to 0 DEG C, be added dropwise mesyl chloride 22g (0.192ml), finish and be stirred to react 30min, be passed through ammonia (1~ 1.5bar), TLC monitoring reaction, 6 it is small when after, the reaction was complete, and stopping is passed through ammonia, and reaction solution decompression filters, and adds in water 100ml* 2 washings, separate dichloromethane phase, and rotation adds in isopropyl acetate 60ml heating for dissolving into steaming excess, be cooled to except dichloromethane 0~5 DEG C of crystallization filters, dry, get Bu Waxitan sterlings (32g) 0.151mol chemical purities 99.8%, optical purity 99.6%.
Embodiment 9
The preparation of Bu Waxitan
Compound D 44g (0.206mol) are added in into 500ml reaction bulbs, dichloromethane 264ml is stirred molten after addition Solution, reaction temperature control to 0 DEG C, be added dropwise thionyl chloride 24.5g (0.206ml), finish and be stirred to react 30min, be passed through ammonia (1~ 3bar), TLC monitoring reaction, 6 it is small when after, the reaction was complete, and stopping is passed through ammonia, and reaction solution decompression filters, and adds in water 100ml*2 Washing, separates dichloromethane phase, and rotation adds in isopropyl acetate 60ml heating for dissolving into steaming excess, be cooled to 0 except dichloromethane ~5 DEG C, crystallization filters, dry, get Bu Waxitan sterlings (33g) 0.155mol chemical purities 99.6%, optical purity 99.5%.

Claims (9)

1. a kind of preparation method of lactam intermediate structural formula D compounds, which is characterized in that structural formula C compounds are in solvent In, by heavy metal catalyst and chiral induction agent, hydrogenating reduction, obtain lactam intermediate structural formula D compounds
2. the preparation method of lactam intermediate structural formula D compounds as described in claim 1, it is characterised in that：Described is molten Agent is selected from water, methanol, ethyl alcohol, isopropanol, propyl alcohol, butanol, isobutanol, acetone, tetrahydrofuran, acetonitrile and Yi Shang solvent Mixed solvent.
3. the preparation method of lactam intermediate structural formula D compounds as described in claim 1, it is characterised in that：The weight Metallic catalyst is selected from palladium carbon, palladium, platinum carbon, platinum, ruthenium carbon, rhodium carbon, palladium aluminium oxide, palladium silica, palladium barium carbonate, palladium carbon acid Calcium, hydroxide palladium carbon, palladium dioxide.
4. the preparation method of lactam intermediate structural formula D compounds as described in claim 1, it is characterised in that：The hand Property derivant be formic acid, citric acid, malonic acid, succinic acid, 1,3,5-triazines -2,4, tri- thioketones trisodium salt (cas 17766- of 6- Mixture 26-6) or more.
5. the preparation method of lactam intermediate structural formula D compounds as described in claim 1, it is characterised in that：The hand Property derivant the mass ratio of quality and compound C be no more than 5.
6. the preparation method of lactam intermediate structural formula D compounds as described in claim 1, it is characterised in that：The hydrogen Atmospheric pressure is no more than 5bar.
7. the preparation method of lactam intermediate structural formula D compounds as described in claim 1, it is characterised in that：The reaction Temperature is -20~50 DEG C.
8. a kind of preparation method of Bu Waxitan, it is characterised in that：Include the following steps：It is characterized in that：Include the following steps： Preparation method according to claim 1~7 any one obtains lactam intermediate structural formula D compounds, by structural formula D Compound is mixed with solvent, adds in activator, is passed through ammonia reaction to get Bu Waxitan.
9. the preparation method of Bu Waxitan as claimed in claim 8, it is characterised in that：The activator is thionyl chloride, careless Acyl chlorides, phosphorus oxychloride, mesyl chloride, the solvent are halogenated alkane, and the reaction temperature is -20~30 DEG C.
CN201810148128.0A 2018-02-13 2018-02-13 A kind of preparation method of high chiral purity lactam intermediate and Bu Waxitan Pending CN108101823A (en)

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CN201810148128.0A CN108101823A (en) 2018-02-13 2018-02-13 A kind of preparation method of high chiral purity lactam intermediate and Bu Waxitan
CN201811465520.4A CN109516943B (en) 2018-02-13 2018-12-03 Preparation method of lactam intermediate with high chiral purity and brivaracetam
EP18906460.3A EP3778568B1 (en) 2018-02-13 2018-12-17 Method of preparing high chiral purity lactam intermediate and brivaracetam
US17/059,125 US11952341B2 (en) 2018-02-13 2018-12-17 Method of preparing high chiral purity lactam intermediate and brivaracetam
PCT/CN2018/121624 WO2019157856A1 (en) 2018-02-13 2018-12-17 Method of preparing high chiral purity lactam intermediate and brivaracetam
CA3103280A CA3103280C (en) 2018-02-13 2018-12-17 Method of preparing high chiral purity lactam intermediate and brivaracetam

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WO2019157856A1 (en) * 2018-02-13 2019-08-22 扬州奥锐特药业有限公司 Method of preparing high chiral purity lactam intermediate and brivaracetam
CN110606817A (en) * 2018-06-14 2019-12-24 广东东阳光药业有限公司 Refining method of brivaracetam
CN111333563A (en) * 2018-12-19 2020-06-26 上海科胜药物研发有限公司 Preparation method of brivaracetam intermediate
WO2020143674A1 (en) * 2019-01-09 2020-07-16 Fujian Haixi Pharmaceuticals Co., Ltd Compounds and their use in the synthesis of brivaracetam apis
CN111943880A (en) * 2019-05-14 2020-11-17 浙江京新药业股份有限公司 Buvalracetam crystal and preparation method and application thereof
CN113651745A (en) * 2021-09-09 2021-11-16 上海医药工业研究院 Buvalracetam intermediate, preparation method and purification method thereof
CN114394921A (en) * 2022-02-22 2022-04-26 浙江九洲药业股份有限公司 Preparation method of high-purity brivaracetam
CN116041240A (en) * 2023-02-17 2023-05-02 扬州奥锐特药业有限公司 Asymmetric catalytic hydrogenation synthesis method of brivaracetam intermediate

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US20230242481A1 (en) * 2020-06-15 2023-08-03 Zhejiang Tianyu Pharmaceutical Co., Ltd. Preparation Method For Brivaracetam

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CN106748950B (en) 2017-01-13 2019-09-03 成都美域高制药有限公司 A kind of preparation method of Bu Waxitan and its intermediate
CN108101823A (en) 2018-02-13 2018-06-01 扬州奥锐特药业有限公司 A kind of preparation method of high chiral purity lactam intermediate and Bu Waxitan
CN108101824B (en) 2018-02-13 2020-04-03 扬州奥锐特药业有限公司 Preparation method of lactam intermediate with high chiral purity and brivaracetam

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WO2019157856A1 (en) * 2018-02-13 2019-08-22 扬州奥锐特药业有限公司 Method of preparing high chiral purity lactam intermediate and brivaracetam
US11952341B2 (en) 2018-02-13 2024-04-09 Yangzhou Aoruite Pharmaceutical Co., Ltd. Method of preparing high chiral purity lactam intermediate and brivaracetam
CN110606817A (en) * 2018-06-14 2019-12-24 广东东阳光药业有限公司 Refining method of brivaracetam
CN110606817B (en) * 2018-06-14 2023-01-24 广东东阳光药业有限公司 Refining method of brivaracetam
CN111333563B (en) * 2018-12-19 2023-11-07 上海科胜药物研发有限公司 Preparation method of buvaracetam intermediate
CN111333563A (en) * 2018-12-19 2020-06-26 上海科胜药物研发有限公司 Preparation method of brivaracetam intermediate
CN112955430A (en) * 2018-12-19 2021-06-11 浙江华海药业股份有限公司 Preparation method of brivaracetam and intermediate thereof
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WO2020143674A1 (en) * 2019-01-09 2020-07-16 Fujian Haixi Pharmaceuticals Co., Ltd Compounds and their use in the synthesis of brivaracetam apis
CN112154140A (en) * 2019-01-09 2020-12-29 福建海西新药创制有限公司 Compound and application thereof in synthesizing bulk drug of Brivaracetam (Brivaracetam)
CN112154140B (en) * 2019-01-09 2023-11-24 福建海西新药创制股份有限公司 Compound and application thereof in synthesizing Brivaracetam (Brivaracetam) bulk drug
CN111943880A (en) * 2019-05-14 2020-11-17 浙江京新药业股份有限公司 Buvalracetam crystal and preparation method and application thereof
CN113651745A (en) * 2021-09-09 2021-11-16 上海医药工业研究院 Buvalracetam intermediate, preparation method and purification method thereof
CN114394921A (en) * 2022-02-22 2022-04-26 浙江九洲药业股份有限公司 Preparation method of high-purity brivaracetam
CN116041240A (en) * 2023-02-17 2023-05-02 扬州奥锐特药业有限公司 Asymmetric catalytic hydrogenation synthesis method of brivaracetam intermediate
CN116041240B (en) * 2023-02-17 2024-04-09 扬州奥锐特药业有限公司 Asymmetric catalytic hydrogenation synthesis method of brivaracetam intermediate

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CA3103280A1 (en) 2019-08-22
US20230066606A1 (en) 2023-03-02
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